Jagadeesh Panda^¹ , P. Venkat Rao^¹*, S. Mukunda Valli^², T. Prabhakar^³, S. Suneetha^³

¹Raghu College of Pharmacy, Dakamarri, Visakhapatnam.

²Yalamarty Pharmacy College , Tharluwada ,Visakhapatnam.

³A.U.College of Pharmaceutical Sciences, Andhra University, Visakhapatnam.

Abstract

Paliperidone is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. Chemically, it is the major metabolite of the widely used atypical antipsychotic drug, resperidone. Paliperidone is indicated for acute and maintenance treatment of schizophrenia. Paliperidone-ER (sold as INVEGA) is the first oral atypical antipsychotic with an extended release, which is achieved by osmotic-controlled release oral delivery system. Paliperidone is a centrally active dopamine Type 2 (D2) antagonist which is metabolized by dealkylation, hydroxylation, dehydrogenation and benzisoxazole scission.Paliperidone gradually rise to reach peak plasma concentration (Cmax ) approximately 24 hours after dosing. The maximum pharmacokinetics of paliperidone administration are dose-proportional within the recommended clinical dose range (3 to 12 mg).The terminal elimination half-life of paliperidone is approximately 23 hours

Keywords

Paliperidone; risperidone; antipsychotic; schizophrenia

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Copy the following to cite this article: Panda J , Rao P. V , Valli S. M, Prabhakar T , Suneetha S. Clinical and Pharmacological Review on Novel Atypical Antipsychotic Drug: Paliperidone. Biomed Pharmacol J 2008;1(1).

Copy the following to cite this URL: Panda J , Rao P. V , Valli S. M, Prabhakar T , Suneetha S. Clinical and Pharmacological Review on Novel Atypical Antipsychotic Drug: Paliperidone. Biomed Pharmacol J 2008;1(1). Available from: http://biomedpharmajournal.org/?p=292

Introduction

Paliperidone, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one is an atypical antipsychotic which is indicated in the treatment of schizophrenia as well as manic and mixed episodes occurring in conjuction with Bipolar I Disorder and depression^1-2. Paliperidone is a risperidone with an extra hydroxyl group i.e, 9-hydroxyrisperidone. Paliperidone-extended release (ER) is achieved by the osmotic-controlled release (OROS), a well established technology already in use for CNS drugs¹. Paliperidone exhibits powerful efficacy for many patients experiencing symptoms of schizophrenia including those who may benefit from a change in therapy.

Chemical Structure

Systematic (IUPAC) name⁷

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one

Scheme 1 Click here to View scheme

Molecular Formula

C₂₃H₂₇FN₄O₃      

 Molecular Mass

426.49          

Physical Properties

Solubility

Paliperidone is a white to yellow non-hygroscopic powder. It is sparingly soluble in 0.1N HCl and methylene chloride. It is insoluble in water, 0.1N Sodium Hydroxide and hexane; and slightly soluble in N,N-dimethylformamide.

Stability

Paliperidone remains stable at normal conditions of temperature and pressure.

Identification

The identification of paliperidone includes tests for appearance (visual examination), identification by IR (Ph. Eur) and HPLC, heavy metals (USP), residue on ignition and sulphated ash (USP ), water content by (Karl-Fischer), assay (HPLC), related substances (HPLC), residual solvents (GC) and particle size (Laser diffraction)².

Dosage Forms And Strengths¹

INVEGA^® Extended-Release Tablets are available in  3 mg (white), 6 mg (beige), and 9 mg (pink). All tablets are capsule shaped and are imprinted with either “PALI 3”, “PALI 6”, or “PALI 9”.

Dose And Administration

The recommended dose of paliperidone Extended-Release Tablets (INVEGA) is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from higher doses; up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be sufficient. When dose increases are indicated, small increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day¹.

Paliperidone ER tablet can be taken with or without food. It must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. 

Pharmacology

Mechanism of action

The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug’s therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D₂) and serotonin Type 2 (5HT_2A) receptor antagonism.

Pharmacodynamics

Primary pharmacodynamics

Paliperidone is a centrally active dopamine Type 2 (D₂) antagonist and with predominant serotonin Type 2 (5HT_2A) activity. Paliperidone is also active as an antagonist at α₁ and α₂ adrenergic receptors and H₁ histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or β₁– and β₂-adrenergic receptors³.

The binding profiles for paliperidone, its enantiomers  and risperidone are comparable. Several in vivo studies were performed in rats and dogs. In rats, paliperidone was slightly less potent than risperidone at early time intervals, but became equipotent at later time intervals, probably reflecting a slower rate of brain penetration. In dogs, paliperidone, its enantiomers and risperidone were roughly equipotent against apomorphine-induced emesis².

Secondary pharmacodynamics

Dopamine secreted in the portal hypophyseal circulation inhibits prolactin release. By antagonizing this tonic inhibitory action of endogenous dopamine, D2 receptor antagonists elevate prolactin release. Anti-adrenergic and anti-histaminergic effects are suspect to elicit hypotensive and sedative effects. Hyperprolactinemia is expected due to the D₂-receptor antagonism.

Pharmacokinetics

Paliperidone is presented as a prolonged-release formulation. The goal of the development program was to identify an extended-release formulation that would enhance the initial tolerability and permit initiation of treatment at an effective dose without the need for initial dose titration. Invega prolonged release tablets are based on the patented OROS^® (Oral Osmotic System) Push-Pull^TM technology delivery system, designed to deliver the paliperidone active substance in a controlled manner over 24 hours, thereby achieving an effective once-a-day treatment for schizophrenia¹⁰.

Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (Cmax ) approximately 24 hours after dosing. The maximum pharmacokinetics of paliperidone administration are dose-proportional within

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